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Extensive epidemiological studies suggest that the diabetic population is at higher risk of site-specific cancers. The diabetes–cancer link has been hypothesized to rely on various hormonal (insulin, IGF1, adipokines), immunological (inflammation), or metabolic (hyperglycemia) characteristics of the disease and even on certain treatments. Inflammation may have an important but incompletely understood role. As a growth factor, insulin directly, or indirectly through IGF1, has been considered the major link between diabetes and cancer, while high glucose has been considered as a subordinate cause. Here we discuss the evidence that supports a role for insulin/IGF1 in general in cancer, and the mechanism by which hyperglycemia may enhance the appearance, growth and survival of diabetes-associated cancers. High glucose triggers several direct and indirect mechanisms that cooperate to promote cancer cell proliferation, migration, invasion and immunological escape. In particular, high glucose enhancement of WNT/β-catenin signaling in cancer cells promotes proliferation, survival and senescence bypass, and represents a previously unrecognized direct mechanism linking diabetes-associated hyperglycemia to cancer. Increased glucose uptake is a hallmark of tumor cells and may ensure enhanced WNT signaling for continuous proliferation. Mechanistically, high glucose unbalances acetylation through increased p300 acetyl transferase and decreased sirtuin 1 deacetylase activity, leading to β-catenin acetylation at lysine K354, a requirement for nuclear accumulation and transcriptional activation of WNT-target genes. The impact of high glucose on β-catenin illustrates the remodeling of cancer-associated signaling pathways by metabolites. Metabolic remodeling of cancer-associated signaling will receive much research attention in the coming years. Future epidemiological studies may be guided and complemented by the identification of these metabolic interplays. Together, these studies should lead to the development of new preventive strategies for diabetes-associated cancers.
Laboratory of Cellular Biology of Hypertension and Molecular Medicine, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
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Laboratory of Cellular Biology of Hypertension and Molecular Medicine, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
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Laboratory of Cellular Biology of Hypertension and Molecular Medicine, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
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Laboratory of Cellular Biology of Hypertension and Molecular Medicine, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
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Laboratory of Cellular Biology of Hypertension and Molecular Medicine, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
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Laboratory of Cellular Biology of Hypertension and Molecular Medicine, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
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Laboratory of Cellular Biology of Hypertension and Molecular Medicine, Department of Medicine, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada
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, Gasalla-Herraiz J, Ding KH, Min L & Isales CM 2000 Glucose-dependent insulinotropic peptide signaling pathways in endothelial cells. Peptides 21 1427 –1432.
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histidine isoleucine (PHI)/peptide histidine methionine (PHM), growth hormone-releasing hormone (GHRH), secretin (SCT), glucagon (GCG), glucagon-like peptide 1 (GLP1), glucagon-like peptide 2 (GLP2), and glucose-dependent insulinotropic peptide (or gastric
Human Gene and Cell Therapy Center, Division of Endocrinology and Metabolism, Division of Child Neurology, Department of Urology, Akdeniz University Hospitals and Clinics, B Block, 1st floor, Campus, Antalya 07058, Turkey
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Human Gene and Cell Therapy Center, Division of Endocrinology and Metabolism, Division of Child Neurology, Department of Urology, Akdeniz University Hospitals and Clinics, B Block, 1st floor, Campus, Antalya 07058, Turkey
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Human Gene and Cell Therapy Center, Division of Endocrinology and Metabolism, Division of Child Neurology, Department of Urology, Akdeniz University Hospitals and Clinics, B Block, 1st floor, Campus, Antalya 07058, Turkey
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patients with T2D ( Dejager & Schweizer 2012 ). GLP1 is naturally released from the gut into circulation after a meal. Because natural peptide forms of GLP1 and glucose-dependent insulinotropic peptide (GIP; incretins) are quickly destroyed by dipeptidyl
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. ( https://doi.org/10.1073/pnas.2022120118 ) De Block CEM Dirinck E Verhaegen A Van Gaal LF 2022 Efficacy and safety of high-dose glucagon-like peptide-1, glucagon-like peptide-1/glucose-dependent insulinotropic peptide, and glucagon-like peptide
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Azienda Ospedaliera Universitaria Careggi (AOUC), Careggi Hospital, Florence, Italy
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Azienda Ospedaliera Universitaria Careggi (AOUC), Careggi Hospital, Florence, Italy
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and oxyntomodulin, is secreted from the pancreatic alpha cells under hypoglycaemic conditions to restore blood glucose levels ( Habegger et al. 2010 ). Its secretion is finely regulated by intestinal peptides, such as GLP-1, oxyntomodulin and glucose-dependent
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science, Wako-shi, Saitama, Japan
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J Rasmussen C Coy DH Holst JJ 2008 Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas . Diabetologia 2263 – 2270
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
COMPARE University of Birmingham and University of Nottingham Midlands, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
COMPARE University of Birmingham and University of Nottingham Midlands, Birmingham, UK
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/ion channels. Perhaps the best characterised signals are derived from the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) released from the enteroendocrine L-cells and K-cells, respectively, following food
